An engineered tetra-valent antibody fully activates the Tie2 receptor with comparable potency to its natural ligand angiopoietin-1

• Published in: Scientific reports Vol. 11; no. 1; p. 14021
• Main Authors: Koya, Yukari, Nara, Hiromi, Yagi, Shigenori, Ueno, Chihoko, Kamohara, Masazumi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 07.07.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Angiopoietin; Apoptosis; Diabetes; Diabetes mellitus; Diabetic retinopathy; Edema; Endothelial cells; Epidermal growth factor; Homology; Immunoglobulins; Ischemia; Permeability; Phosphorylation; Protein-tyrosine kinase; Retinopathy; Signal transduction; Therapeutic targets; Tight junctions; Vascular diseases
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-93660-4

Abstract Activation of the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor by angiopoietin-1 (Ang1) is critical for vascular stabilization: it promotes survival signal transduction via auto-phosphorylation and reduces vascular permeability by strengthening tight junctions between endothelial cells. Thus, Tie2/Ang1 signaling is a promising therapeutic target for vascular diseases. However, in vivo use of existing Tie2 signaling modulators, such as recombinant Ang1, is restricted by limitations in manufacturability and stability. Here, we present a novel engineered tetra-valent agonistic antibody, ASP4021, which can specifically and fully activate the Tie2 receptor in an equivalent manner to Ang1. ASP4021 induced Tie2 self-phosphorylation and inhibited apoptosis in a human primary endothelial cell line. Additionally, single administration of ASP4021 significantly suppressed mustard-oil-induced vascular permeability in rats. ASP4021 may thus be a potential therapeutic candidate for diseases associated with vascular weakness such as diabetic retinopathy, diabetic macular edema and critical limb ischemia.